PDCT-10. FIRST IN PEDIATRICS PHASE I STUDY OF CRENOLANIB BESYLATE (CP-868,596-26) ADMINISTERED DURING AND AFTER RADIATION THERAPY (RT) IN NEWLY-DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND RECURRENT HIGH GRADE GLIOMA (HGG) Free

Children diagnosed with DIPG have a median survival of less than one year despite RT, the primary modality of therapy. PDGF pathway activation has been noted in tumor tissue analyzed from approximately 70 % of pediatric DIPG and 50% of HGG patients, suggesting that inhibition of this pathway may be of clinical benefit. Crenolanib is a highly selective antagonist of the PDGF pathway with in vitro IC₅₀ of 35- and 185- fold lower than observed with dasatinib and imatinib, respectively.

We used a rolling-6 design to study the MTD of once-daily crenolanib administered during and after local RT in children with newly diagnosed DIPG (Stratum A), and in recurrent/progressive HGG, including DIPG (Stratum B).We have completed accrual of 55 patients, 30 and 20 evaluable in Stratum A and B, respectively. Serum pharmacokinetic analyses were performed using non-compartmental techniques on all patients for samples collected on days 1 and 28 of course 1.

Fifty evaluable patients were enrolled on the two strata and the maximum tolerated dosage (MTD) of 170 mg/m²has been established in each stratum. Dose limiting toxicities (DLTs) were primarily elevated liver enzymes in both strata (<15% of patients), and the most common Grade 3 toxicity seen on Stratum A was leukopenia that resolved with drug interruption. PFS and OS at 2 years were 8% (± 4.5%) and 22% (±7%) for Stratum A, and 5% (± 3.5%) and 30% (± 9%) for stratum B.

The PK and current preliminary toxicity data indicate that crenolanib is well tolerated in children at doses slightly higher than the established MTD from Phase I trial in adults (280 mg/day).The spectrum of toxicities observed in children is similar to those observed in adults, though leukopenia is a novel toxicity.